GRM7 variants confer susceptibility to age-related hearing impairment.

Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individual's risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.

Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait.

Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment.

Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform.

Occupational noise, smoking, and a high body mass index are risk factors for age-related hearing impairment and moderate alcohol consumption is protective: a European population-based multicenter study.

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss.

HYPOTHESIS: The common GJB2 (Connexin 26) 35delG mutation might contribute to the development of age-related hearing impairment (ARHI) and noise-induced hearing loss (NIHL). BACKGROUND: GJB2, a gene encoding a gap junction protein expressed in the inner ear, has been suggested to be involved in the potassium recycling pathway in the cochlea. GJB2 mutations account for a large number of individuals with nonsyndromic recessive hearing loss, with 35delG being the most frequent mutation in populations of European origin. Other genes involved in potassium homeostasis have been suggested to be associated with ARHI and NIHL, and distortion product otoacoustic emission distortions indicative of hearing loss alterations have been found in 35delG carriers. METHOD: We genotyped 35delG in two distinct sample sets: an ARHI sample set, composed of 2,311 Caucasian samples from nine different centers originating from seven different countries with an age range between 53 and 67 years, and an NIHL sample set consisting of 702 samples from the two extremes of a noise-exposed Polish sample. RESULTS: After statistical analysis, we were unable to detect an association between 35delG and ARHI, nor between 35delG and NIHL. CONCLUSION: Our findings indicate that there is no increased susceptibility in 35delG carriers for the development of ARHI or NIHL.

GJB2 and GJB6 mutations in 165 Danish patients showing non-syndromic hearing impairment.

Thirty-two genes causing non-syndromic hearing impairment (NSHI) have been cloned, including GJB2 and GJB6 encoding the gap junction subunits connexin 26 and connexin 30, respectively. One mutation in GJB2, 35delG, accounts for a large percentage of GJB2 hearing impairment in Southern Europe whereas a considerably lower frequency has been reported from Northern European populations. Recently, a 342-kb deletion implicating GJB6 was found in 22 out of 44 NSHI patients of Spanish origin with only one mutated allele of GJB2. We report the first study of GJB2 and GJB6 mutations in Danish patients with NSHI. We tested 165 individuals and found GJB2 mutations in 16 individuals. The deletion implicating GJB6 was found in two individuals out of 9 heterozygous for GJB2 mutation. Furthermore, we screened 509 unselected samples from the Danish newborn population for the 35delG mutation in GJB2. We found 9 samples heterozygous for 35delG and 11 samples heterozygous for mutations leading to amino acid variants in GJB2 protein. In conclusion, our data are in accordance with results from other Northern European populations. Furthermore, our data on the GJB6 deletion suggest that routine screening for this deletion could help to explain hearing impairment in some Northern European NSHI patients heterozygous for a mutation in GJB2.

The hearing aid revolution: fact or fiction?

OBJECTIVE: To present the experiences of consumers with traditional hearing aids (T-HAs) and digital signal processing hearing aids (DSP-HAs) during the period 1999-2001, based on data obtained from an ongoing quality assurance programme. MATERIAL AND METHODS: A questionnaire is mailed to subjects fitted with HAs 3-4 months after the fitting, and includes questions concerning satisfaction with the HA, frequency of use of the HA, ability to manipulate the HA, satisfaction with the overall services of the department and need (if any) for additional appointments. RESULTS: The response rate was 69.5%, and thus information was obtained from 14 325 subjects (44.9% male, 55.1% female; median age 72 years; range 18-97 years). Of the respondents, 7,983 (55.7%) had been provided with T-HAs and 6,342 (44.3%) with DSP-HAs. The results of the questionnaire were as follows: 71.4% of those fitted with a T-HA were very satisfied/satisfied with it, compared to 68.1% with a DSP-HA (p < 0.05); 91.6% and 89.1%, respectively used their HA daily/weekly (p < 0.05); 80.5% and 82.2%, respectively, were able to manipulate their HA; 96.2% and 97.3%, respectively were satisfied with the overall services of the department; and 32.5% and 48.5%, respectively, indicated a need for an additional appointment (p < 0.05). A comparison between high- and low-cost DSP-HAs showed that 68.4% and 68.2%, respectively were very satisfied/satisfied with their HA (p = NS). CONCLUSIONS: According to consumers the "HA revolution" has failed to materialize; the significantly higher proportion of subjects with DSP-HAs who need an additional appointment represents a heavy burden on the hearing health services. The lack of a difference between the benefits obtained with low- and high-cost DSP-HAs emphasizes the need for appropriately designed and performed trials before new HA technology is launched.

[Hearing loss in children--epidemiology, age at identification and causes through 30 years]. / Høretab hos børn--epidemiologi, identifikation og årsager gennem 30 år.

INTRODUCTION: The survey describes paediatric audiology through 30 years within Copenhagen City concerning epidemiology, age at identification, and causes of permanent hearing impairment in children. MATERIAL AND METHODS: Three longitudinal ten years birth-cohorts [table: see text] are included: 1970-1979 (n = 69); 1980-1989 (n = 64), and 1990-1999 (n = 104) provided with hearing aids, living in the Copenhagen City at the time of the data collection in January 1982, 1992, and 2002. The cohorts 1970-1979 and 1980-1989 have previously been described (1), whereas the 1990-1999 birth cohort is evaluated as part of a prospective registry study. The estimated prevalences are based on the age-matched background population. RESULTS: The estimated prevalence of children provided with hearing aids is 1.97/1000 and the estimated prevalence of congenital hearing impairment is 1.50/1000--without longitudinal changes from 1970-1979 over 1980-1989 to 1990-1999. The proportion of at-risk children in the three-pooled birth-cohorts is 63.3%. The median age at identification of the birth-cohort 1990-1999 was 18 months, 1980-1989 16 months, and 1970-1979 43 months. Only 6% of children with congenital hearing impairment born 1990-1999 are identified at the age of six months, and only 27% at the age of one year. An increase in the prevalence of genetic hearing impairment in the cohort 1970-1979 was demonstrated. DISCUSSION: The prevalence of permanent hearing impairment in childhood through three decades is unchanged, and the age at identification of children with congenital hearing impairments is still delayed. Factors causing hearing impairment demonstrate an increase in genetic factors, which, however, are not significant.

Familial aggregation of pure tone hearing thresholds in an aging European population.

OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated. STUDY DESIGN: Multicenter survey in 8 European centers. SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study. RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies. DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.

GJB2 mutations and degree of hearing loss: a multicenter study.

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Expectations about hearing aids: demographic and audiological predictors.

The Expected Consequences of Hearing Aid Ownership inventory (ECHO) is a 14-item questionnaire for measuring expectations about hearing aids. The objectives of this study were to evaluate the ECHO questionnaire used in the Danish National Hearing Health Service in terms of reliability and validity; to use the inventory to assess the patients' pre-fitting expectations in different domains, to gain information on possible predictors for the magnitude of expectations, and to evaluate whether first-time users had realistic expectations. The questionnaire was administered to 805 consecutive patients, and responses were received from 47.7%, representative for the population examined in the department. The median age was 74.1 years, with an even distribution of males and females, and a median better-ear pure-tone average (0.5-4 kHz) of 41.3 dB HL. The results showed that the questionnaire had acceptable reliability and validity when the original subscales were rearranged. The pre-fitting expectations with regard to the positive effect of amplification and different aspects related to the hearing aid and service were, overall, very high. Age and hearing status were predictors of the magnitude of expectations related to the hearing aid and the service. In first-time users, unrealistic positive expectations were found with regard to potentially negative features of hearing aids.